Project Summary/Abstract Antineutrophil cytoplasmic antibody (ANCA) ? associated vasculitis (AAV) is a group of rare organ-and life- threatening multisystem diseases involving inflammation and destruction of small blood arteries. AAV appears mediated by neutrophils, but the mechanisms underlying the neutrophil infiltration and activation are poorly understood. The disease is treated with glucocorticoids and other anti-inflammatory and immunosuppressive medications. In most cases of new or relapsing AAV, induction of remission in AAV is accomplished by several months of high-dose daily oral glucocorticoids combined with either cyclophosphamide or rituximab, followed by a maintenance phase of treatment with often chronic, daily, low-dose glucocorticoids along with another immunosuppressive agent. Due to the intensity and duration of the treatment with glucocorticoids and high relapse rate, the overall burden to patients in terms of drug toxicity and permanent damage is substantial. Vamorolone is a first-in-class dissociative steroidal drug that has orphan designation with both FDA and EMA and has been granted Fast-Track designation by FDA for first-in-patient studies in Duchenne muscular dystrophy (DMD). Vamorolone shows complete loss of most or all side effects associated with glucocorticoids in both pre-clinical (murine) studies, and human Phase 1 trials to doses 30-times typical glucocorticoid doses. Here, we propose research on banked sera samples from patients with AAV that will lead to an IND and proof- of-concept trial of vamorolone for the treatment of AAV. The proposed research integrates, and creates synergism, between two NIH-funded centers: the NIAMS-supported Vasculitis Clinical Research Consortium (VCRC), and the NICHD Research Program on Developmental Pharmacology, in partnership with the NINDS- funded vamorolone orphan drug development program of ReveraGen Biopharma. We propose to build on our recently-reported glucocorticoid-responsive pharmacodynamic biomarkers in both DMD and pediatric inflammatory bowel disease (IBD) that are in current use in the Phase 2 trials in DMD. In this proposal we plan to use samples from our VCRC Biorepository to carry out i) a validation study of these existing DMD/IBD biomarkers; and ii) deep biomarker discovery of AAV-specific markers of response to glucocorticoids. These cross-disease and vasculitis-specific biomarkers will then be translated to a targeted panel (targeted mass spectrometry, immunoassays [MSD, Luminex, immunoblots]). The deliverable of Aim 1 will be a set of robust, validated pharmacodynamic biomarkers for glucocorticoid response and toxicity; some markers will be common to AAV, DMD, and IBD, and some specific to AAV. We propose in Aim 2 to design a small, short- term, dose-ranging, Phase IIa proof-of-concept clinical trial using these biomarkers as the primary endpoint, and subsequently submit an IND to the FDA for this trial. Both the NIAMS RFA and the 21st Century Cures Act encourages innovative approaches to expediting drug efficacy and safety studies, including the use of fit-for- purpose biomarkers, especially for expansion of labeling; our research plan speaks directly to these goals.